Abstract
Recently,
many
saturated
bioisosteres
of
the
benzene
ring
have
been
developed,
and
their
applications
in
drug
development
evaluated.
Most
these
are
caged
hydrocarbons,
which
rigid
skeletons
three-dimensional
spaces.
Recent
efforts
to
synthesize
hydrocarbons
enabled
access
multi-functionalized
congeners
that
expected
be
(bio)isosteres
benzenes.
This
short
review
summarizes
recently
reported
methods
for
obtaining
(typically
more
than
disubstituted)
hydrocarbons.
1
Introduction
2
Proposed
Structures
Caged
Hydrocarbons
as
Saturated
(Bio)isosteres
Benzene
Ring:
A
Brief
Summary
3
Access
Multi-functionalized
Hydrocarbons:
De
Novo
Synthetic
Approaches
3.1
Bicyclo[1.1.1]pentanes
(BCPs)
3.2
Bicyclo[2.1.1]hexanes
(BCHs)
3.3
Bicyclo[3.1.1]heptanes
(BCHeps)
3.4
Others
4
C–H
Functionalization
5
Conclusion
Chemical Society Reviews,
Год журнала:
2024,
Номер
53(3), С. 1068 - 1089
Опубликована: Янв. 1, 2024
Leveraging
light
energy
to
expose
the
‘dark’
reactive
states
describes
whole
essence
of
triplet–triplet
transfer.
This
offers
an
impressive
opportunity
conduct
a
multitude
diverse
reactions
and
access
sought-after
molecular
motifs.
Angewandte Chemie International Edition,
Год журнала:
2023,
Номер
62(34)
Опубликована: Июнь 12, 2023
Synthesis
of
bicyclic
scaffolds
has
attracted
tremendous
attention
because
they
are
playing
an
important
role
as
saturated
bioisosteres
benzenoids
in
modern
drug
discovery.
Here,
we
report
a
BF3
-catalyzed
[2π+2σ]
cycloaddition
aldehydes
with
bicyclo[1.1.0]butanes
(BCBs)
to
access
polysubstituted
2-oxabicyclo[2.1.1]hexanes.
A
new
kind
BCB
containing
acyl
pyrazole
group
was
invented,
which
not
only
significantly
facilitates
the
reactions,
but
can
also
serve
handle
for
diverse
downstream
transformations.
Furthermore,
aryl
and
vinyl
epoxides
be
utilized
substrates
undergo
BCBs
after
situ
rearrangement
aldehydes.
We
anticipate
that
our
results
will
promote
challenging
sp3
-rich
frameworks
exploration
BCB-based
chemistry.
Angewandte Chemie International Edition,
Год журнала:
2023,
Номер
62(48)
Опубликована: Окт. 12, 2023
Bicyclo[2.1.1]hexanes
(BCHs)
are
becoming
ever
more
important
in
drug
design
and
development
as
bridged
scaffolds
that
provide
underexplored
chemical
space,
but
difficult
to
access.
Here
a
silver-catalyzed
dearomative
[2π+2σ]
cycloaddition
strategy
for
the
synthesis
of
indoline
fused
BCHs
from
N-unprotected
indoles
bicyclobutane
precursors
is
described.
The
strain-release
operates
under
mild
conditions,
tolerating
wide
range
functional
groups.
It
capable
forming
with
up
four
contiguous
quaternary
carbon
centers,
achieving
yields
99
%.
In
addition,
scale-up
experiment
synthetic
transformations
cycloadducts
further
highlighted
utility.
Chemical Science,
Год журнала:
2023,
Номер
14(36), С. 9885 - 9891
Опубликована: Янв. 1, 2023
Crossed
[2
+
2]
cycloaddition
yields
bicyclo[2.1.1]hexanes
with
11
different
substitution
patterns.
ortho
-,
meta
-
and
polysubstituted
benzene
bioisosteres,
structures
substituent
patterns
that
go
beyond
aromatic
chemical
space
can
be
prepared.
Chemical Science,
Год журнала:
2023,
Номер
14(48), С. 14092 - 14099
Опубликована: Янв. 1, 2023
1,2-Disubstituted
bicyclo[2.1.1]hexanes
have
been
synthesized,
characterized,
and
biologically
validated
as
saturated
bioisosteres
of
the
ortho
-substituted
benzene
ring.
Angewandte Chemie International Edition,
Год журнала:
2024,
Номер
63(48)
Опубликована: Сен. 2, 2024
Abstract
The
cycloaddition
reaction
involving
bicyclo[1.1.0]butanes
(BCBs)
offers
a
versatile
and
efficient
synthetic
platform
for
producing
C(sp
3
)‐rich
rigid
bridged
ring
scaffolds,
which
act
as
phenyl
bioisosteres.
However,
there
is
scarcity
of
catalytic
asymmetric
cycloadditions
BCBs
to
fulfill
the
need
enantioenriched
saturated
bicycles
in
drug
design
development.
In
this
study,
an
synthesis
valuable
azabicyclo[2.1.1]hexanes
(aza‐BCHs)
by
enantioselective
zinc‐catalyzed
(3+2)
with
imines
reported.
proceeds
effectively
novel
type
BCB
that
incorporates
2‐acyl
imidazole
group
diverse
array
alkynyl‐
aryl‐substituted
imines.
target
aza‐BCHs,
consist
α‐chiral
amine
fragments
two
quaternary
carbon
centers,
are
efficiently
synthesized
up
94
%
96.5:3.5
er
under
mild
conditions.
Experimental
computational
studies
reveal
follows
concerted
nucleophilic
ring‐opening
mechanism
This
distinct
from
previous
on
Lewis
acid‐catalyzed
BCBs.
Journal of the American Chemical Society,
Год журнала:
2025,
Номер
unknown
Опубликована: Янв. 2, 2025
We
recently
reported
a
chiral
phosphoric
acid
(CPA)
catalyzed
enantioselective
photomediated
ring
contraction
of
piperidines
and
other
saturated
heterocycles.
By
extruding
single
heteroatom
from
ring,
this
transformation
builds
desirable
C(sp3)–C(sp3)
bonds
in
the
contracted
products;
however,
origins
enantioselectivity
remain
poorly
understood.
In
work,
has
been
explored
across
an
expanded
structurally
diverse
substrate
scope,
revealing
wide
range
enantioselectivities
(0–99%)
using
two
distinct
CPA
catalysts.
Mechanistic
investigations
support
rate-determining
excitation
that
generates
short-lived
achiral
intermediates
are
intercepted
by
enantiodetermining
closure.
The
effects
competitive
uncatalyzed
reactivity
light-driven
reversibility
closure
on
have
elucidated.
Statistical
models
were
built
regressing
scope
against
key
structural
features
products
for
both
resultant
suggested
factors
influence
response
each
catalyst
enabled
rational
modification
pharmaceutically
relevant
target
molecule
to
improve
enantioselectivity.
Finally,
density
functional
theory
(DFT)-based
transition
state
analysis
identified
noncovalent
interactions
with
correlated
unique
selectivity-relevant
uncovered
through
statistical
modeling.
Our
findings
not
only
offer
comprehensive
insight
into
system
but
should
also
aid
future
development
related
CPA-catalyzed
reactions.